Inhaled anesthesia associated with reduced mortality in patients with stage III breast cancer: A population-based study

Background Patients diagnosed with stage III breast cancer often undergo surgery, radiation therapy, and chemotherapy as part of their treatment. The choice of anesthesia technique during surgery has been a subject of interest due to its potential association with immune changes and prognosis. In this study, we aimed to compare the mortality rates between stage III breast cancer patients undergoing surgery with propofol-based intravenous general anesthesia and those receiving inhaled anesthetics. Methods Using data from Taiwan’s National Health Insurance Research Database and Taiwan Cancer Registry, we identified a cohort of 10,896 stage III breast cancer patients. Among them, 1,506 received propofol-based intravenous anesthetic maintenance, while 9,390 received inhaled anesthetic maintenance. To ensure comparability between the two groups, we performed propensity-score matching. Results Our findings revealed a significantly lower mortality rate in patients who received inhaled anesthetics compared to those who received propofol-based intravenous anesthesia. Sensitivity analysis further confirmed the robustness of our results. Conclusions This study suggests that inhaled anesthesia technique is associated with a lower mortality rate in clinical stage III breast cancer. Further research is needed to validate and expand upon these results.

metric, the inclusion of other outcomes, such as progression-free survival, would have enriched the oncological context of our research.Regrettably, our database did not house this specific data, precluding us from analyzing secondary endpoints.A notable strength of our investigation lies in leveraging a national database.Gathering extensive data on stage III breast cancer from a singular institution can be formidable, often spanning numerous years.The national database enabled us to obtain a comprehensive view of stage-specific breast cancers.While previous research has often amalgamated early and late-stage breast cancer responses to anesthesia, we specifically examined late-stage responses.Given existing literature that highlights differential immune reactions in early versus late cancer stages, our focused approach augments the understanding of anesthesia responses in advanced breast cancer.

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We have expanded the 'Limitations' section in the 'Discussion' from lines 224 to 240.

Reviewer 2:
The strength is that the data from Taiwan's National Health Insurance Research Database and Taiwan Cancer Registry probably are of good quality, as far as can be judged from abroad -definitely, the amount of data is impressive.The background information on possible mechanisms behind the finding is satisfactory, although we have many more mechanisms to digest regarding the possible "good" properties of propofol in terms of a possible beneficial effect in cancer surgery.Today, no one can say with certainty which mechanism(s) are actually of clinical importance.The weakness of the study is that the study is retrospective, and therefore, the result just gives us a hint of what might be the truth.So regardless of whether both the data quality and the amount of data are satisfactory, and that the statistical and epidemiological methodology is good with e.g.propensity score matching, the retrospective design, and not least important, the use of inhalation anaesthetics or propofol for maintenance of anaesthesia was of course not randomised (and the proportion of patients who received propofol was relatively small) means that the results must be taken with a large pinch of salt.
Q1. Another topic to comment on is the identification of stage III cancer as a specific entity.As far as I can tell, as a simple anaesthetist, the authors want us to believe that stage III cancer is well defined.The TNM system, found in Table 1, illustrates that stage III cancer is not quite homogeneous: Stage IIIA breast cancer is the same as: T0 N2 M0, T1 N2 M0, T2 N2 M0, T3 N1 M0, T3 N2 M0.Stage IIIB is the same as: T4 N0 M0, T4 N1 M0, T4 N2 M0.Stage IIIC is the same as: Any T N3 M0.Response: The reviewer's observation regarding the subdivision of stage 3 breast cancer into categories 3A, 3B, and 3C is indeed well-founded.Each category can be ber 5, 2023 2/5 further delineated into distinct classifications based on the tumor size and nodal involvement (TN categories).If one were to parse out each TN category for detailed analysis, the resulting subpopulations would be exceedingly small, presenting considerable statistical challenges due to limited sample sizes which may not yield statistically significant results.Therefore, in our study, we have adopted an approach in Table 1 that focuses on broader trends by initially comparing outcomes within the entirety of stage 3 patients.Specifically, we have directed our analysis towards discerning the differences between patients with pronounced tumor size (T category) and those with extensive nodal involvement (N category).This strategy allows us to observe overarching patterns and potential prognostic differences in survival and outcomes between these two subsets of patients with advanced disease.This methodological decision enables us to maintain statistical robustness while still providing insightful distinctions within a broadly defined patient cohort.
Q2.Although I have been doing part-time research for 30+ years, I am still a simple anaesthetist without advanced knowledge of statistics and epidemiology.So, you may excuse me for asking about the statistical adjustment of the propensity score matched cohort.Isn't adjusting an already "adjusted" cohort the same as over-adjusting?
Response: Thank you for your insightful comments regarding the application of propensity-score matching (PSM) and the subsequent use of multivariate analysis in our study.Under ideal circumstances, PSM would indeed obviate the need for further multivariate analysis, as it aims to simulate a randomized controlled trial by creating a balanced cohort in which the treatment and control groups are matched on confounding variables.In such a scenario, univariate and multivariate analyses would, theoretically, yield consistent results.However, the inherent complexity of real-world data often precludes the achievement of perfect balance between groups, even after meticulous propensity score matching.Subtle imbalances may persist due to unmeasured confounders or the limited overlap in the distribution of propensity scores, which can result in residual confounding.The decision to perform additional multivariate analysis post-PSM in our study is a deliberate one, intended to enhance the robustness of our analytical approach.By incorporating multivariate analysis, we aim to control for any remaining imbalances and confirm the consistency of the PSM results.This step is particularly crucial given the assumption of the PSM that all confounders are measured and correctly included in the model.The multivariate analysis provides an additional layer of adjustment, mitigating the impact of any potential unobserved heterogeneity.Furthermore, multivariate analysis allows us to assess the effect of each covariate on the outcome, controlling for other variables, which is especially important when the propensity score model may not fully account for the complexities of the data.This approach acknowledges the propensity of real-world data to defy the strict assumptions of statistical models and seeks to solidify the conclusions drawn from the observed associations.We believe that this complementary use of PSM followed by multivariate analysis does not reflect a lack of confidence in the matching process but rather a prudent acknowledgment of the limitations inherent in observational data.It is a strategy designed to ensure that our findings are not only statistically sound but also as close to the underlying biological reality as possible.
If this manuscript is intended to reach clinicians, I am not satisfied with the method of presenting the difference between the cohorts.We clinicians are more likely to understand differences when they are expressed as five-year survival (or for that matter mortality), or even more interestingly in the case of breast cancer, ten-year survival.
ber 5, 2023 3/5 To summarise, I would like to see: Q3.A more humble discussion considering the retrospective design.
Actions: We have expanded the 'Limitations' section within the 'Discussion' to encompass lines 224 to 230, with a particular emphasis on the limitations inherent in retrospective studies.
Q4.A discussion of the heterogeneity hidden in the concept of stage III cancer.
Actions: We have extended the 'Limitations' section in the 'Discussion' to cover lines 230 to 237, with specific focus on the inherent heterogeneity within the classification of stage III cancer.
Q5.A consideration of a more clinically appropriate presentation of the difference in mortality (or survival) between the groups.
Actions: Thanks for great suggestion!We have included both 3-year and 5-year mortality rates, as these metrics are more readily comprehensible to physicians.Q2.What are the different factors that contribute to the selection of a particular method, such as IA and IV? Which method is mostly/generally preferred for breast cancer patients?
Response: Breast cancer surgeries employ various anesthetic techniques, including regional anesthesia, IV sedation, general anesthesia, and combinations thereof.Stage III breast cancer surgeries, which often encompass complex procedures like Modified Radical Mastectomy(MRM), breast-conserving surgery(BCS) with sentinel lymph node biopsy(SLND), BCS with lymph node dissection, or reconstruction, primarily utilize general anesthesia.These procedures are typically lengthier than those for stages I or II, where BCS+SLND is more common.Research suggests that anesthetic choice doesn't significantly influence post-surgery breast pain.Therefore, the selection between regional and general anesthesia is often guided by clinicians' preferences, with the latter being the prevalent choice.Within general anesthesia, two primary techniques are used: inhalational and total intravenous anesthesia (TIVA).Both techniques have long-standing safety records.The choice is often dictated by specific patient-related factors, such as the risk of post-operative nausea and vomiting or the uncommon risk of malignant hyperthermia.It's pertinent to note the ongoing debate regarding the influence of anesthetics on cancer and immune responses.In the backdrop of Taiwan's healthcare system, the introduction of Processed EEG Monitoring in 2007 marked a shift in favor of TIVA.However, TIVA lacks the minimal alveolar concentration (MAC) that was traditionally employed for depth monitoring and is generally costlier than inhalational methods.Additionally, Processed EEG Monitoring remains an ber 5, 2023 out-of-pocket expense for breast cancer surgery in Taiwan.Considering the heightened risk of post-operative nausea and vomiting among Asian breast cancer patients, propofol-based general anesthesia has gained traction.However, its impact on cancer outcomes is still a subject of debate, which underpins the essence of our study.
research article has only two figures.It would be helpful to readers if the author could mention the current global status of breast cancer by showing a figure.Other figures might include the different methods of Anesthesia used during breast cancer surgery.Actions: We have included Fig 1 to illustrate the global status of breast cancer.Additionally, Fig 2 has been added to provide an overview of the topic addressed in this manuscript.